Intravenous lipid emulsions (IVLEs) have been used in the clinical setting for over 40 years. By substitution of a portion of the calories derived from carbohydrate, IVLEs have significantly reduced the clinical complications associated with hypertonic glucose infusions as part of TPN therapy (Driscoll, D. F., 1990, DICP. Ann. Pharmacother. 24, 296-303.) In particular, hyperglycemia significantly increases the risk of infectious complications (Khaodhiar, L., McCowen, K., Bistrian, B. R., 1999, Curr. Opin. Clin. Nutr. Metab. Care 7, 79-82). Moreover, as long as the rate of lipid infusion from long-chain triglycerides (LCTs) does not exceed 0.11 g/kg/h, major toxicities such as immune dysfunction and pulmonary gas diffusion abnormalities are avoided (Klein, S., Miles, J. M., 1994, J. Parenter. Enteral Nutr. 18, 396-397).
Providing IVLEs continuously as an all-in-one admixture fosters a safe administration rate that minimizes infusion-related complications, yet can induce emulsion instability (Driscoll, D. F., Adolph, M., Bistrian, B. R., 2000, in: Rombeau, J. L., Rolandelli, R. H. (Eds.), Clinical Nutrition—Parenteral Nutrition. WB Saunders Company, Philadelphia, Pa., USA). Alternative lipid emulsion mixtures containing medium-chain triglycerides (MCTs) may reduce the toxicity associated with pure LCT-based lipid emulsions (Smyrniotis, V. E., et al., 2001, Clin. Nutr. 20, 139-143) and may also yield more stable all-in-one admixtures (Driscoll, D. F., Bacon, M. N., Bistrian, B. R., 2000, J. Parenter. Enteral Nutr. 24, 15-22). Nevertheless, it is the ultimate goal of the pharmacist to assign a beyond-use date to such compounded preparations that ensures the admixture does not progress to a state that produces clinically-evident adverse effects (Driscoll, D. F., 1995, Nutr. Clin. Pract. 10, 114-119).
The physicochemical stability of IVLEs is crucial to their safety, as the coalescence of colloidally stable submicron lipid droplets (<1 μm) forming oversized fat globules (>5 μm) in the large diameter tail of the particle size distribution may be trapped in the pulmonary microcirculation (Globule Size Distribution in Intravenous Emulsions, 1998, Proposed (Chapter 729), in-process revision, Pharmacopoeial Forum, vol. 24, pp. 6988-6994.). As the internal diameter of the pulmonary capillaries is between 4 and 9 μm, the intravenous infusion of unstable lipid emulsions may produce an embolic syndrome. Thus, any critical assessment of IVLE stability and safety must include this remote population of unstable fat globules for active signs of coalescence manifested by an expanding population of oversized fat globules in the large-diameter tail of the droplet size distribution. The usual volume-weighted percent of fat (PFAT) globules found in the large diameter tail (>5 μm) of commercially available IVLEs ranging in concentrations of 100-300 g/l (10, 20 and 30% w/v formulations), has been shown to be as low as 0.001% up to 0.05% (Driscoll, D. F., et al., 2001, Int. J. Pharm. 219, 21-37). In stable all-in-one admixtures with much lower final lipid concentrations commonly ranging from 20 to 50 g/l (2-5%), these volume-weighted values are similar, i.e. PFAT>5 μm are <0.1% for 24-30 h at room temperature (Driscoll, D. F., Bacon, M. N., Bistrian, B. R., 2000, J. Parenter. Enteral Nutr. 24, 15-22; Driscoll, D. F., et al., 2001, Clin. Nutr. 20, 151-157).
However, when the growth of fat globules in the large diameter tail progresses to a PFAT>5 μm of 0.4% or higher, the emulsions exhibit signs of phase separation and was originally suggested to be a ‘threshold’ concentration that defines the pharmaceutical instability of IVLEs (Driscoll, D. F., et al., 1995, Am. J. Health Sys. Pharm. 52, 623-634). Clearly, this definition focuses on a quantitatively small fraction of the total population of lipid droplets in the emulsion, as the vast majority of these are <1 μm (i.e. >99% of the total fat present). For example, at the proposed threshold of pharmaceutical instability (PFAT>5 μm=0.4%), only 0.08-0.2 g/l of free oil are in the large diameter tail of the globule size distribution based on typical final lipid concentrations in all-in-one admixtures. Although the amounts of free oil present are relatively small at this pre-selected threshold, it is a quantitatively significant population of enlarged fat globules, largely spanning a size range between 5 and 20 μm and containing 105-106 globules/ml. If inadvertently administered by intravenous infusion, it might produce an embolic syndrome given the typical flow rates of TPN infusions.
Generally, all-in-one admixtures are given as 24-h continuous infusions, and in adults often range from 42 to 125 ml/h (1-3 l/day) or in pediatric patients from 2 to 20 ml/h (50-500 ml/day). Thus, the cumulative dose of enlarged fat globules (i.e. PFAT>5 μm) from unstable all-in-one admixtures is capable of saturating the perfused surface area of the pulmonary microvasculature. The precise toxic parenteral dose of coalesced fat globules >5 μm is not known, but such globules are likely to be most dangerous in either critically ill patients and/or those with pre-existing pulmonary disease (El-Ebiary et al., 1995, Crit. Care Med. 23, 1928-1930; Driscoll, D. F., 1997, Nutrition 12, 166-167 Editorial; Moore, F. A., 2001, Crit. Care Med. 29, 1644-1645 Editorial).
Clearly, large fat globules >5 μm are likely less toxic than similarly sized precipitates, such as dibasic calcium phosphate crystals, owing to the flexibility of the globules in the former example compared to the rigidity of the solid particles in the latter case. Nevertheless, because of the potentially adverse clinical consequences and insidious nature of unstable IVLEs, the principal focus of our investigations are on the extent of coalescence by changes in the large diameter tail (PFAT>5 μm) of the globule size distribution rather than on earlier stages of emulsion instability (i.e. aggregation).
The present inventors have previously demonstrated that IVLEs containing physical mixtures of MCTs and LCTs are more stable than pure LCTs in both high (Driscoll et al., 2000, J. Parenter. Enternal Nutr. 24, 15-22) and low osmolality (Driscoll, D. F., et al., 2001, Clin. Nutr. 20, 151-157) all-in-one admixtures. To further investigate the stabilizing influence of MCTs on emulsion stability, the present inventors have now studied these effects using a low osmolality all-in-one admixture with two types of MCT-LCT physical mixtures; one single emulsion formulation containing these oils versus two extemporaneously compounded formulations containing different ratios of MCT and LCT prepared from two separate starting emulsions. This was performed in order to investigate whether the method of emulsion preparation and/or the ratio of MCT to LCT affected the otherwise stabilizing influence of MCTs on all-in-one admixtures previously demonstrated. The present inventors have now demonstrated that the method of emulsion preparation is important in affecting the stabilizing influence of MCTs and have extended the beneficial effects for these mixtures intended for critically ill, premature and newborn infants.
It should be noted that previous studies involving parenteral nutrition (PN) admixtures have largely involved admixtures intended for adults. PN admixtures intended for very young patients (neonate to the first year of life) have a very different final composition compared to those prescribed for older children and adults. This is primarily the result of differences in the amino acid profiles and certain electrolyte concentrations conventionally used in each population. Contrasted with adults, the pediatric amino acid profiles have a higher content of branched-chain amino acids (i.e., leucine, isoleucine and valine) and contain taurine. In addition, the amino acid cysteine, which is found in very small quantities in some commercial adult products, is often added extemporaneously as the hydrochloride salt in pediatric formulations, and in specific proportions to the amounts of protein prescribed in order to achieve nitrogen balance (NATIONAL ADVISORY GROUP ON STANDARDS AND PRACTICE GUIDELINES FOR PARENTERAL NUTRITION (1998) JPEN 22: 49-66).
Consequently, the pediatric amino acid formulations are more acidic than those used in adults. Of all the additives that can comprise a PN admixture (i.e., amino acids, dextrose, lipids, electrolytes, vitamins and minerals), only commercial amino acid formulations contain a sufficient quantity of buffers that ultimately determines the final pH of the admixture. Thus, because of the composition differences between adult and pediatric amino acid formulations, the final pH of PN admixtures comprised for adults are characteristically between 5.8-6.4, whereas for very young children they are between 4.8-5.4. In addition, because the caloric requirements for newborns are 4-6 times higher per kilogram than adults, these admixtures often have very different macronutrient profiles that may also affect all-in-one (AIO) stability. Although the final proportions of carbohydrate and lipid calories are similar to adults, the amount of protein for a given level of energy intake in the very young is lower. For example, if adults are fed at 25 kcal/kg and receive 1.5 g/kg of protein, the typical calorie-nitrogen (C:N) ratios in adults are ˜80-100:1, compared to infants fed at 120 kcal/kg and 3.0 g/kg of protein, with a corresponding C:N ratio of ˜225-250:1. Finally, another important difference between adult and pediatric parenteral nutrition formulations is the daily amounts of certain essential electrolytes. For example, the parenteral equivalent of the recommended dietary allowance (RDA) for calcium in adults is in the range of 2.5-7.5 mmol/day, whereas for pediatric patients the range is between 10-15 mmol/day (NATIONAL ADVISORY GROUP, supra). Consequently, given the importance of amino acid (Washington C, et al. (1991) Int. J. Pharm. 77: 57-63) and electrolyte (Washington C. (1992) Int. J. Pharm. 87: 167-74) concentrations to AIO stability, these formulations have not been used in the neonatal and infant populations due to the major compositional differences (lower pH, low final amino acid concentration, high final calcium concentration) compared to adults.
Thus, the separate infusion of intravenous lipid emulsions (IVLEs) is common practice in the acute care of very young patients, yet is associated with significant morbidity and mortality (Freeman J, et al. (1990) N. Engl. J. Med. 323: 301-8; Avila-Figueroa C, et al. (1998) Pediatr. Infect. Dis. J. 17: 10-17; Matlow A G, et al. (1999) Infect. Contr. Hosp. Epidem. 20: 487-93).
The present inventors have previously demonstrated that IVLEs consisting of both medium-chain triglycerides (MCTs) and long-chain triglycerides (LCTs) have produced more stable AIOs in both high and low osmolality formulations in adults, where pure LCT-based AIOs have often failed (Driscoll D F, Bacon M N, Bistrian B R. (2000) JPEN 24: 15-22; Driscoll D F, et al. (2001) Clin. Nutr. 20: 151-57). As the present inventors now show, however, the stabilizing effect of MCTs on AIOs is dependent on the mode of preparing the formulations.
Moreover, the present inventors also now show that MCT-containing IVLEs can be used in AIOs for the very young, that is, for young patients weighing 1, 2.5 and 5 kg, to provide the macronutrient profile required for the very young and to minimize the risks of infection attendant to the separate administration of lipid emulsions.
Use of the present invention provides several benefits, including but not limited to the following:                Reduction in the risk of infections associated with the separate administration of lipid emulsions;        Improved metabolic utilization (e.g. oxidation) of the infused lipid emulsion over 24 hours versus shorted time intervals and therefore less adverse effects;        Providing more appropriate infusion rates and less n-6 LCT % s to thereby provide less stimulation of eicosanoid production and therefore and thus less potential for adverse effects;        Providing more stable lipid emulsions and reducing the risk of embolization associated with less stable lipid emulsions made from pure LCTs; and        Improving the ability to meet the special nutritional needs of a pediatric patient by providing intravenous nutritional support.        